FoxP2 is currently the only molecule directly linked to a developmental onset human speech and language disorder. In affected individuals, a mutation of the FoxP2 gene causes problems in sequencing muscle movements required for articulating speech sounds, as well as wider deficits in linguistic and grammatical processing. In addition, it is known that genetic risk factors play a role in autism spectrum disorders. Hallmarks of autism include late language onset and other deficits in social communication. The proposed research will provide new insights into the genetic basis of the aforementioned disorders, further characterizing the role of FoxP2 as well as possibly uncovering the involvement of new genes in these disorders. Similarities between human speech and birdsong make songbirds a unique model system to test molecules involved in language and social communication using molecular, physiological, and behavioral analyses. FoxP2 shows overlapping neural expression in the brains of zebra finches and human embryonic striatum. Furthermore, in the adult zebra finch brain, song practice changes FoxP2 mRNA and protein levels. This proposal encompasses three specific aims;1) disruption of normal vocal learning in juvenile zebra finches, 2) genetic analysis of these birds, as well as controls, using microarray technology, and 3) the identification of groups of genes that co-vary in their expression levels, and analysis of differences in these gene groups in experimental birds as compared to controls. In light of the fact that a single mutation in the FoxP2 gene in humans results in severe speech and language deficits, we expect to find FoxP2 at the center of some group of genes involved in sensorimotor learning. Findings will further characterize the role of FoxP2 in vocal learning, as well as provide new candidate genes for study using molecular techniques. This project falls under the auspices of the NIMH institute mission and strategic plan (2001) to support research on "how specific behaviors are directed and influenced by genes (including inheritability), how behavior can modify brain biology... how behavioral strategies for the prevention of diseases can be refined" and investigation of cognitive processes including mechanisms for neural plasticity. PUBLIC HEALTH RELEVANCE We must understand how the normal and mutated forms of these genes and their gene targets operate in animal models like the songbird. This will facilitate the development of therapeutic interventions to treat these cognitive deficits in afflicted humans. The proposed research will contribute to the understanding of neural mechanisms underlying human speech and associated autism spectrum